Among a few oral and maxillofacial pathologists with a Ph.D. degree in the field of Immunology and Oral Biology, the candidate seeks to develop an independent research career focusing on the diagnosis and treatment of oral, head & neck cancer. The candidate has been continuously productive, and published in well-respected peer-reviewed journals on the topics highly relevant to this application. Under the mentorship of Dr. Robert Ferris, a leading head and neck surgeon-scientist, the candidate has made novel discoveries in head and neck squamous cell carcinoma (HNC) cells to support this application. With synergistic mentorship from a fully integrated five-member committee with broad expertise to cover every aspect of this application, this award allows the candidate to develop new experimental skills and knowledge of cancer immunology, endoplasmic reticulum (ER) stress signaling, and translational HNC research. Additional mentored training in a prominent HNC program, at the University of Pittsburgh, is conductive for high quality translational research and the development of scientific leadership skills of the candidate. HNC is the sixth most common human cancers with frequent resistance. The epidermal growth factor receptor (EGFR) monoclonal antibody, cetuximab, shows promising therapeutic efficacy in about 20% of HNC patients. Cetuximab suppresses tumor growth by inhibition of EGFR signaling and activation of cellular immunity targeting cancer cells. However, the 80% non-response rate suggests an intrinsic resistance mechanism. Autophagy has been shown to be hijacked by multiple solid tumors to endure therapy-induced inflictions. Recent study shows that autophagy induction in tumor cells dampens their susceptibility to immune effector cells, and that inhibition of autophagy sensitizes HNC cells to cetuximab. However, the lack of mechanistic insight into the autophagy machinery in HNC cells renders the targeting of this mechanism remarkably unspecific and ineffective. Our long-term goal is to leverage molecules involved in autophagy to improve systemic therapy against HNC. A recent study reveals an autophagy-promoting mitochondrial protein complex centering on NLRX1 and TUFM proteins. We hypothesize that specific inhibition of autophagy, by targeting the NLRX1-TUFM complex, sensitizes HNC cells to cetuximab. Three aims are put in place: (1) we will assess the role of NLRX1-TUFM complex in modulating the effects of EGFR blockade in vitro; (2) we will investigate the role of autophagy in modulating HNC patients' responses to cetuximab; (3) we will validate the therapeutic potential of targeting NLRX1-TUFM in vivo, and explore the mechanisms this complex employs to engage EGFR blockade-induced autophagy. Completion of this project will provide novel insights into the autophagy machinery of HNC cells and identify potential therapeutic targets to improve a cetuximab-based regimen.